A team of Toronto scientists is pushing Alzheimer's research in a radical new direction - testing whether electrodes implanted deep in patients' brains can jolt their memories into good working order.
The procedure, known as deep brain stimulation, aims to repair faulty nerve circuits with steady electrical pulses from two noodle-thin metal rods buried beneath the cortex. The rods connect to a cable that snakes out of the head and down the neck to a battery-operated regulator embedded below the collarbone. Most often the DBS system is used to treat chronic pain and Parkinson's disease and in research against intractable depression.
But at the University Health Network - after an intense 18-month ethics review - researchers have performed DBS as an experimental brain surgery on six patients in the early stages of Alzheimer's disease.
The small, world-first trial, published Wednesday in the Annals of Neurology, found DBS is a relatively safe procedure for people with Alzheimer's, which affects about 500,000 Canadians. But no one knows yet if it will also prove to be an effective one.
Based on results of a standard test known as the Mini-Mental Exam, two patients deteriorated after a year of stimulation, two showed no change, while two improved. The average Alzheimer's patient declines by three points per year, even with standard medications, which all six patients continued to take during the trial.
Exactly how or why electricity might bolster a brain struck with Alzheimer's, however, is as mysterious as the disease itself - which after more than 100 years of study, still defies explanation. But the Toronto research team of neurologists, psychiatrists and geriatricians feels the Phase 1 results warrant a Phase 2 study and hopes to find funding to test DBS in another 50 early Alzheimer's patients. (Patients at the earliest stage of the disease seemed to respond best to DBS in the trial.)
"This has to be pursued to find out if it is valuable or not," said Andres Lozano, the neurosurgeon and senior scientist who led the study, which ran between 2005 and 2008, at Toronto Western Hospital. "It's not more of the same; it's a very bold, aggressive approach that seems reasonably safe."
With the number of Alzheimer's patients set to triple within 25 years, and nothing close to a cure - or even an effective treatment - in the medicine cabinet, the Toronto experiment is emblematic of the urgency sweeping the field. It's also a sign of a certain willingness to think far outside the box.
"The first time I presented this to anybody, they thought, 'this is absolutely nuts,'" Dr. Lozano said in an interview this week. He acknowledged that any talk of brains and electricity might conjure bad memories of electroshock therapy's ugly history, and he admits he has heard from skeptics in the Alzheimer's community who feel the procedure sounds "far out."
But, "given that there are no effective treatments we have to explore all possibilities," he said, "and this has quite a strong scientific rationale." He added that a research group in France and another at Johns Hopkins University in Baltimore are interested in launching their own trials.
Dr. Lozano, who holds the Canada Research Chair in Neuroscience, first considered DBS for Alzheimer's in 2003. At the time, he had a conscious, 400-pound patient on the operating table hoping to use DBS to suppress the man's appetite. But when he zapped a brain structure in the patient's hypothalamus, instead of describing food cravings, the man described vivid details of a date in a park he had more than 20 years ago.
That structure turned out to be a thick bundle of more than a million nerve fibres called the fornix, the main highway in and out of the memory circuits of the hippocampus. Dr. Lozano compared it to the record button on a tape recorder, involved in "laying down of memories."
"No one thought you could activate these circuits on an ongoing basis, and DBS gave us the tool," he said.
From this, a hypothesis was born. Since the hippocampus is often hit hard and fast in people with Alzheimer's, which progresses to shrink, tangle and silence various brain regions, Dr. Lozano and his team wondered if electrodes implanted in the fornix could somehow recharge memory circuits before the disease causes full destruction.
Landing ethics approval, however, was, he says, "no slam dunk." For one, gaining informed consent from patients who in some cases forgot they had ever heard of DBS posed particular challenges. In follow-up, some forgot they underwent the procedure and were surprised by the chest-embedded regulators, which require new batteries at least every five years.
As a result, the team also worked with surrogates - patients' spouses or children - to support the procedure and an international ethics review panel ultimately voted 6-4 to four to allow the trial to go ahead.
Dr. Lozano said approval came on the basis that Alzheimer's is a devastating sentence for families and patients, who usually die within nine years of a diagnosis. As well, DBS for other conditions has been generally safe for the 80,000 people who have undergone it worldwide and the procedure - which costs roughly $20,000 - is reversible.
It took Robert Linton just three seconds to say yes. Even after they told him about the two holes they would have to drill through his head.
He was 62 then, and he'd just heard the A-word. A former city councillor in Brampton, Ont., Mr. Linton had been helping out on an election campaign when someone called his wife, told her "something's wrong with Bob." He was acting odd, forgetting stuff. His wife, Barb, sent him to the doctor who diagnosed him with Alzheimer's.
"It knocks your feet out from under you," he said.
The future flashed before his sea blue eyes - withering in a nursing home, "brain rotting away." Then it was the past - a city council debate about the millions needed to build nursing homes for all the people with Alzheimer's. Now he was one of them.
When the doctor mentioned they were trying "new things" at Toronto Western Hospital, Mr. Linton couldn't wait to sign up. The 64-year-old father of two, whose mental exam score increased after receiving DBS in 2008, has now become the public face of the daring experiment.
"I'm convinced it's working for me," Mr. Linton said, tapping his head after a hospital press conference Wednesday.
So far, the team has found no serious adverse effects. But when the electrodes are turned up to near maximum voltage, heart rate and blood pressure can be affected. As well, a high voltage can also produce spontaneous and powerful recollections.
On the operating, table, as doctors investigated higher voltage levels, Mr. Linton relived a fishing trip he once had with his son, a memory so clear he made the motions of reeling in a fish - "a muskie …"
But Dr. Lozano explained that the voltage is usually kept at a low setting. "We don't necessarily want people walking around thinking that they're fishing."
The only side effect Mr. Linton described Wednesday is waking in the night with rich recollections of visiting old friends - "good memories, pleasant memories," he said.
Dr. Lozano suspects that while the electrodes reside in one brain area, they also boost activity in other brain regions. Imaging scans showed brain areas that looked dormant before DBS, were reawakened after the implants and remained active one year later.
Neuroscientist Jack Diamond, scientific director of the Alzheimer's Society of Canada, cautioned that brain scan changes are important only if they translate into behavioural improvements. "What you do to the brain doesn't matter, it's what you are doing to the patient that matters."
Still, Dr. Diamond called the DBS report "interesting and worth pursuing … but we need a lot more work here."
If nothing else, Mr. Linton says the implants have given him hope. A former real-estate agent and owner of a bookstore chain, Mr. Linton teared up describing how it feels to wake up "alive every morning." He pays daily visits to the YMCA, plays computer games and chats with friends.
"I've never been so fit," he said. "I want to make it to 100."Report Typo/Error
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